Pooh and friends travel to Egypt in Biblical times. The first song ("Deliver Us") shows Hebrew slaves labor away while Jochebed (also spelled Yocheved) and Pooh and friends see mothers' baby sons being taken away from them, as Pharaoh Seti I has ordered his guards to kill all the male Hebrew babies of Egypt to prevent any future rebellion led by Hebrew men. Yocheved thus places her own son in a basket and sets it afloat on the Nile to be preserved by fate, singing her final lullaby ("River Lullaby", A recurring motif in the film) to the baby. Winnie and Yocheved's daughter, Miriam, follows the basket and witnesses her baby brother being taken in by the Queen of Egypt and named Moses.
The story cuts to 40 years later (according to the Bible), to show a grown Moses and his foster-brother, Rameses II, racing their chariots through the Egyptian temples, destroying many statues. When they are lectured by their father, Seti I, later on for their misdeeds, Rameses is offended. Moses later remarks that Rameses wants the approval of his father, but lacks the opportunity. Moses goes to cheer his brother up, making joking predictions ("Statues crumbling and toppling, the Nile drying up; you will singlehandedly bring the greatest kingdom on Earth to ruins!"). That is when Moses meets Pooh and his friends. They then stumble in late to a banquet given by Seti, discovering that he has named Rameses as Prince Regent. In thanks, Rameses appoints Moses as Royal Chief Architect. As a tribute to Rameses, the high priests Hotep and Huy offer Tzipporah, a Midian girl they kidnapped, as a concubine for him, Rameses rejects the offer and gives Moses the sacrifice. She eventually escapes, with Moses' help. Moses and Pooh are led to a small spot in Goshen where he is reunited with Miriam and Aaron, his siblings. There, Miriam tells him the truth about his past with Pooh's help since he was a witness those years ago. Moses at first is in denial ("All I Ever Wanted"), but a nightmare and talks with his adoptive parents help him realize the truth. Moses eventually kills an Egyptian guard, who was abusing an old slave, and runs away in exile, with Pooh and friends following him.
Moses finds his way to Midian, as Tzipporah's sisters are under attack by bandits. Pooh tries to fight them as The Masked Bear, but Moses saves them. He is welcomed warmly by Tzipporah's father, Jethro the High Priest of Midian. Moses becomes a shepherd and eventually marries Tzipporah ("Through Heaven's Eyes"). Moses and Pooh soon come into contact with the burning bush while chasing a stray lamb and are instructed by God to free the slaves from Egypt. God then imbues Moses' shepherding staff with the power to do great wonders, the greatest being to shepherd his people to freedom. Tzipporah returns with him to find the slaves in even worse condition than before. He discovers that Rameses is now Pharaoh and has a wife and a young son. Moses tells Rameses to let his people go, demonstrating the power behind him by changing his shepherding staff into a snake. Hotep and Huy boastfully repeat this transformation ("Playing with the Big Boys Now"), invoking all of Egypt's gods in the process; behind their backs, the snake created by Moses eats both of their snakes. Rather than being persuaded, Rameses is hardened and orders the slaves' work to be doubled.
Out in the work field, Moses is struck down by an elder Hebrew into a muddy pit, and then is confronted by Aaron, who blames him for the excess workload. Moses, with Miriam's help, tells the Hebrews to believe that freedom will come. He and Pooh confront Rameses, who is passing on his boat in the Nile. Rameses orders his guards to bring Moses to him, but they turn back when Moses turns the river into blood. After nine of the Plagues of Egypt occur ("The Plagues"), leaving Egypt in ruins, Moses returns to Rameses to warn him about the final plague. After an almost-tender moment between the ex-brothers, Moses is told never to come to Rameses again, even though Moses warns Rameses that an even worse plague is about to transpire, and to think of his only son. Moses then instructs the Hebrews to paint lamb's blood above their doors for the coming night of Passover. The LORD then sent the final plague through during the night, killing all the firstborn children of Egypt. Moses and Pooh once more visits the grief-stricken Rameses, who is cradling the body of his own son. Rameses reluctantly lets the Hebrews go, and Moses leaves and breaks down in tears outside.
The next morning, the Hebrews happily pack, leave their enslavement, and eventually find their way to the Red Sea ("When You Believe"), but turn around to find out Rameses has changed his mind and is pursuing them with his army. Moses parts the Red Sea, while behind him a pillar of fire writhes before the Egyptians, blocking their way. The Hebrews cross on the sea bottom; when the army gives chase, the water closes over the Egyptians, and the Hebrews are freed. Rameses, who has been hurled back to the shore by the collapsing waves, is left yelling his brother's name in disgrace. Moses turns from the shore and begins to lead his people onward; only briefly looking back towards the sea in Rameses' direction, murmuring sadly; "Good bye, Brother". The last scene of the film shows Moses delivering the Ten Commandments to his people as Jochebed's voice echoes in the background.